The phosphoinositide 3-kinases (PI3Ks) are a family of enzymes involved in cellular function such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. And the PI3Ks utilize both lipid and protein kinase activity to regulate numerous intracellular signal transduction pathway, which in turn coordinate a range of downstream cellular processes.
The PI3K family is divided into three classes (I, II, and III). The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity. Class I PI3Ks have received the most attention from the scientific community and are further broken down into two subclasses, 1A and 1B, which are responsible for the production of Phosphatidylinositol 3-phosphate (PI(3)P), Phosphatidylinositol (3,4) -bisphosphate (PI(3,4)P2), and Phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) (Vanhaesebroeck et al., Trends Biochem. Sci., 1997, 22(7), 267-272; Leslie et al., Chem. Rev., 2001, 101(8), 2365-2380) (FIG. 1).

The class IA isoforms, PI3Kα, PI3Kβ, and PI3Kδ, are primarily activated by protein tyrosine kinase-coupled receptors, whereas the sole class IB member, PI3Kγ is activated by G-protein coupled receptors (GPCRs), such as chemokine receptors (Leevers S J et al., Current Opinion in Cell Biology 1999, 11(2) 219-225). Class IA PI3K is composed of a heterodimer between a p110 catalytic subunit and a p85 regulatory subunit (Carpenter C L et al., J. Biol. Chem. 1990, 265(32), 19704-19711). There are five variants of the p85 regulatory subunit, designated p85α, p55α, p50α, p85β, or p55γ. There are also three variants of the p110 catalytic subunit designated p110α, β, or δ catalytic subunit. The first three regulatory subunits are all splice variants of the same gene (Pik3r1), the other two being expressed by other genes (Pik3r2 and Pik3r3, p85β, and p55γ, respectively). The most highly expressed regulatory subunit is p85α; all three catalytic subunits are expressed by separate genes (Pik3ca, Pik3cb, and Pik3cd for p110α, p110β, and p110δ, respectively). The first two p110 isoforms (α and β) are expressed in all cells, but p110δ is expressed primarily in leukocytes, and it has been suggested that it evolved in parallel with the adaptive immune system. The regulatory p101 and unique catalytic p110γ subunits comprise the type IB PI3K and are encoded by a single gene each. Each isoforms have unfolded the close connections between PI3Kα with oncogenesis, PI3Kβ, with thrombosis, PI3Kδ, with immune function and PI3Kγ with inflammation by pathophysiologic studies. Class II PI3Ks include PI3K C2a, C2p and C2y subtypes, which are characterized by containing C2 domains at the C terminus. The substrate for class III PI3Ks is PI only.
Wortmannin and LY294002 are well known and studied as a first generation PI3K inhibitor. Wortmannin was first isolated from Penicillium wortmanni in 1957 (Brian, P. W. et al., Bri. Mycol. Soc., 1957, 40, 365-368), but the structure was recognized in 1974 (Wiesinger, D. et al., Cell Mol. Life. Sci., 1974, 30, 135-136). It was reported for the anti-inflammatory activity (Wiesinger, D. et al, Experintia, 1974, 30, 135-136) and identified as a PI3K inhibitor (Powis, G. et al., Cancer Res., 1994, 54, 2419-2423). LY294002 is the first synthetic PI3K inhibitor with a quercetin modified chemical structure. LY294002 wa first described as a competitive PI3K inhibitor in 1994 (Vlahos, C. J. et al., J. Biol. Chem., 1994, 269, 5241-5248).
Compounds suitable as PI3K inhibitors are also disclosed in WO 07/044,729; WO 08/152,390; WO 08/070,740; WO 09/039,140; WO 09/052,145; WO 09/143,317; WO 10/002,954; WO 10/037,765; WO 10/091,996; WO 10/100,144; WO 10/135,014; WO 10/144,513; WO 10/102,958; WO 10/133,318 and WO 10/007,099.